Preparation for intratracheobronchial administration

ABSTRACT

A preparation for intratracheobronchial administration comprising a powder preparation for intratracheobronchial administration contained in a receptacle composed essentially of hydroxypropyl methyl cellulose.

TECHNICAL FIELD

The present invention relates to a preparation for intratracheobronchialadministration. More specifically, the present invention relates to apreparation for intratracheobronchial administration, comprising apowder preparation for intratracheobronchial administration contained ina receptacle composed of at least one component selected from the groupconsisting of hydroxypropyl methyl cellulose, methyl cellulose,hydroxypropyl cellulose, starches, hydroxypropyl starches, and sodiumalginate. Furthermore, specifically, the present invention is concernedwith a preparation for intratracheobronchial administration, containedin a receptacle, in which a medicament in the powder preparation forintratracheobronchial administration is contained in the receptaclecomposed of at least one component of cellulose derivatives-analogues,that is, selected from the group consisting of hydroxypropyl methylcelluloses, methyl celluloses, hydroxypropyl celluloses, starches,hydroxypropyl starches, and sodium alginate, and the medicament is noteasily adhered to the receptacle so that the amount of theintratracheobronchially delivered medicament is improved.

BACKGROUND ART

The airway extending from the nasal cavity, oral cavity to the pharynx,larynx, trachea, bronchia, bronchioles, and alveoli is a passageway forexpiratory and inspiratory air.

In the airway, there occur many diseases such as nasal allergies,asthma, bronchitis, lung emphysema, and the like. The method foradministering a medicament in the pharmacotherapy for these diseases maybe classified into the whole body administration such as the use oforally administered medicaments and injections, andintratracheobronchial local administration such as the use of nebulas,inhalants, and the like.

Oral administration is an easy method, and the use of injections ensuresthe absorption of the injections into the body, and therefore, theseadministering methods have widely been employed. However,intratracheobronchial administration of a medicament is highly valuablein the light of convergence of the medicament into an acting site,reduction of adverse side effects due to the convergence, andfast-acting properties of the effect of the medicament.

Further, in addition to the local administration of a medicament forsuch diseases as mentioned above, which occur in the airway, there hasrecently been a trial of proceeding a medicament from alveoli to bloodby utilization of the fact that the barrier between the alveoli andblood is dwarfish, and the intratracheobronchial administration has nowattracted public attention as a systemic administration method forpeptides, proteins or the like, which are metabolized in thegastrointestinal tract, liver or the like so as to be inactivated, whenthese are orally administered.

In addition, there have been attempts to locally administer a vaccine inthe airway by utilizing the antigen recognizing function of thelymphatic system in the airway, so as to prevent and treat a disease.Therefore, it may be said that the importance of intratracheobronchialadministration is very significant.

The preparations for intratracheobronchial administration to be used forthe above intratracheobronchially administering method can be classifiedinto the following two kinds, with respect to the properties of theparticles of the preparations: (1) preparations, the droplets of whichare deposited to the inside of the airway, and (2) preparations, thefine solid particles of which are deposited to the inside of the airway.

A preparation (1) is usually an aqueous solution containing amedicament, which is atomized by a nebulizer, and inhaled into theairway as minute droplets. Preparations (2) are further roughlyclassified into (i) aerosol preparations, in which the fine solidparticles are contained in a pressure container in a state such thatthey are dispersed in a fluorohydrocarbon, and when they are dischargedout of the vessel in the case of the use thereof, these particles movein the airway together with the fluorohydrocarbon, and after thefluorohydrocarbon has rapidly evaporated, they are finally deposited inthe airway, as fine solid particles of the medicaments, and (ii) powderpreparations in which a medicament is contained as fine solid particlesin receptacle, and in the case of using any of them, the fine solidparticles of the medicament are inhaled into the airway directly fromthe container or by use of an administration utensil, by injection orinhalation of breath, and deposited to the inside of the airway as finesolid particles of the medicament.

These preparations have already been put to practical use, regarding allthe types thereof. The liquid preparations of (1) require a nebulizer oratomizer and are therefore, not convenient to carry. Thefluorohydrocarbon aerosol preparations of (2)-(i) are simple to handle,and have been widely used, but there has arisen a trend of publicopinion to restrict the use of these preparations, considering theproblem of air pollution from fluorohydrocarbon gases. Under suchcircumstances, powder preparations for intratracheobronchialadministration of (2)-(ii), which have remained comparatively backwardin the development as compared with the other two kinds of preparations,have come to noticeably attract public attention.

In order to administer a powder preparation for intratracheobronchialadministration, a receptacle for the powder preparation and anadministering utensil are needed. In the following, the "receptacle"means a receptacle in which the powder preparation is directlycontained, and the powder preparation is contained in the receptacle,after it has been prepared by mixing and stored until it is used.Therefore, the receptacle is ordinarily tightly sealed. In addition, theadministering utensil in the present invention is generally a device fortaking the powder preparation out of the above-mentioned receptaclescontaining the powder preparation in such a state as can be administeredinto the airway; it is, e.g., a device for maintaining the tightlysealed powder preparation at a proper position, and boring a hole in thereceptacle so as to enable the powder preparation to proceed into theairway. The receptacle and administering utensil are usually separatelyproduced, but they may be produced as an integrated product. Forexample, a part of a receptacle is removed when using the powderpreparation, so as to produce a hole, whereby it becomes possible tocause the powder preparation contained in the receptacle to move intothe respiratory tract from the receptacle.

The powder preparation, which has been made movable into the airway fromthe receptacle by use of an administering utensil or by performing someoperations in an integrated product of a receptacle and administeringutensil, is delivered into the airway by utilization of the inhalationof the breath of the user (patient) or of a gas from a pressurized gascylinder or by some other device.

The receptacle and administering utensil for the powder preparation forintratracheobronchial administration are classified into the followingtwo types according to the dose of the powder preparation in thereceptacle: (i) a type in which the dose of the powder preparation to bedelivered into the airway per one time has preliminarily been set apartand contained in each receptacle (unit dose type), and (ii) a type inwhich a multidose of the powder preparation is contained in thereceptacle, and dose of the powder preparation is divided up by somemeans and sent into the airway every time the preparation is to be used(multidose type).

For the above two types of containing systems, there have been devisedmany administering utensils, and as specific examples thereof, there maybe mentioned, e.g., as a unit dose type, the powder medicine-dispensingdevice disclosed in Japanese Examined Patent Publication (Kokoku) No.63-6024, "Spinhaler" (Registered Trade Mark), "Rotahaler" (RegisteredTrade Mark), "Diskbaler" (Registered Trade Mark) or the like describedin "Respiratory Drug Delivery" edited by P. R. Byron, published by CRCPress, 1990, p.169, and as a multidose type, "Turbohaler" (RegisteredTrade Mark) described on p.169 of the same publication, and the like.

The shapes of receptacles for containing a powder preparation vary inmany ways depending on the above containing systems or the structure ofthe administering utensils. As the unit dose type receptacles, therehave hitherto been known, e.g., hard medical capsules which have beenwidely used for oral preparations; disk-shaped molded products which canbe charged in a "Diskhaler" (Registered Trade Mark); and disposablereceptacles as proposed in WO 89/01348 Specification. In addition, asmultidose type receptacles, there have been known the receptacles ofsuch shapes as can be changed in conformity with the structure of anadministering utensil and a predetermined amount of the content of thereceptacle can be moved from the administering utensil to the airway. Inthe present invention, there may be used any of the receptacles of theseshapes. In addition, a receptacle may constitute a part of anadministering utensil. For example, a receptacle may be cylindrical and,simultaneously, have a structure such that the receptacles can beremoved from its cap and fixed to an administering utensil by driving ascrew.

On the other hand, with respect to the material of a receptaclecontaining the powder preparation, even if the present powderpreparation is in the form of an inhalant that is administered into theairway of the human body, the receptacles are in direct contact with thepowder preparation. Accordingly, as the materials which havespecifically been known as those of the receptacles containing powderpreparations, in consideration of safety and the like, there may bementioned, as unit dose type ones, hard gelatin medical capsules whichhave widely been used for oral preparations; aluminium to be molded intoa disk-shaped product (see e.g.p.169 of the above-mentioned publicationpublished by R. Byron); or plastics, mainly polyolefinic ones such aspolyethylene, polypropylene, and polystyrene, which have been proposedfor disposable receptacles. In addition, as the materials of multidosetype receptacles, there may be mentioned plastics, mainly polyolefinicones such as polyethylene, polypropylene, and polystyrene; aluminium;glass; and the like.

As the powder preparations to be contained in the receptacles made ofvarious materials, there have been known powder of a medicament itselfalone, which is administered into the airway and deposited thereto,whereupon the effect of the medicine is exhibited at an affected part orthe preparation is transferred to the whole body from the affected partand the effect of the medicines exhibited in the whole body, or mixturesthereof with an appropriate diluent, e.g. lactose, mannitol, crystallitecellulose and the like.

With respect to such a powder preparation for intratracheobronchialadministration, since it is necessary to reach a target region with goodefficiency and broaden the deposited area at the reached region, theparticle diameter of the powder should be reduced. The interrelationbetween the particle diameter of the particles and the region attainedby the preparation has been examined by many investigators, and thoughtheir reported values are not always consistent with other, it is saidthat, for example, particles with a particle diameter larger than 10 μm,but up to about 500 μm, are deposited mainly in the oral cavity andnasal cavity, particles with a particle diameter above 2 μm and not morethan 10 μm are deposited mainly in the trachea, bronchi, and bronchiolesand those having a particle diameter ranging from 0.5 to 2 μm aredeposited mainly in the alveoli. (see "The Newest Biopharmacology"edited by Awazu and Koizumi, published by Nankodo Publishers, 1991,p.67). The above-mentioned particle size is applied to a medicamentparticle alone in the powder preparation and a particle comprising amedicament, but not to an additive particle.

According to the technique regarding the above powder preparation forintratracheobronchial administration, the present inventors havecontinued their studies concerning the administration of powdermedicaments into the nasal cavity, bronchi, alveoli or the like, andbeen confronted with significant technical problem on the basis of thefact that the above-mentioned powder preparation is a powder of fineparticles.

That is, it has been found that, while a powder preparation is containedin the above-mentioned various receptacles and stored, or while it ischarged in administering utensils, the powder preparation comes incontact with the receptacle owing to vibration, so that the fineparticles of a medicament or fine particles comprising a medicamentbecome adsorbed and adhered to the receptacle surfaces. It has been alsofound that when administering a medicament into the airway, even if thepowder preparation contained in the receptacles is introduced into theairway by utilization of a gas pressurized by inhaled breath or somemeans, the fine particles adsorbed and adhered to the receptacle innersurfaces remain in the receptacles as such, so that the preparation doesnot reach the airway.

The above problem is quite insignificant, in the case of an oralpreparation, which is to be administered together with the receptaclescontaining said preparation, even if the preparation is adsorbed andadhered to the inner surfaces of the receptacles, but in the case of apowder preparation for intratracheobronchial administration, in whichthe contents alone of the receptacles, not the receptacles themselves,are administered into the interior of the body, the amount of deliveredcontent into the body is reduced, the problem becomes such a seriousproblem as may give an influence to the therapeutic effect of thepreparation.

As a means of settling the present problem, there have hitherto beenexamined usually conceivable methods, such as a method of making fineparticles, e.g. a method of enlarging the density of the powderpreparation, a method of preliminarily adhering and adsorbing especiallyfine particles of the powder preparation to comparatively largerparticles in the powder preparation, and the like, and it has been madeclear that some methods are effective and the present problem has beensettled e.g. in the case of corticosteroid preparation forintranaso-oral spraying administration. However, even if any of theabove-mentioned methods is employed, depending upon the kind of amedicament, e.g. in peptides and proteins which exhibit noticeableabsorptivity and adhesion properties to gelatin or plastics, therecannot be avoided adhesion and adsorption thereof to receptacles. Inaddition, when the powder preparation is kept under dried conditionsespecially for improvement of the physicochemical stability, it is verydifficult, according to the above method, to prevent the powderpreparation from being adhered and adsorbed to the receptacles.

Therefore, there have been demanded preparations forintratracheobronchial administration, which do not require troublesomeformation of fine particles, which may be applied to variousmedicaments, and which are not adsorbed or adhered to the internalsurfaces of the receptacles. There have been demanded also preparationsfor intratracheobronchial administration, which are not adsorbed oradhered to the inner surfaces of the receptacles, even under driedconditions.

Incidentally, the technical concept of employing hydroxypropyl methylcellulose or the like as the material of receptacles for a medicament isalready known. For example, Japanese Unexamined Patent Publication No.61-100519 discloses medical hard capsules composed essentially ofhydroxypropyl methyl cellulose.

On the other hand, it has already been known that various kinds of unitdose type receptacles and various multidose type receptacles, includingmedical hard capsules, have been used as receptacles for powderpreparations for intratracheobronchial administration.

However, until now, it has not been a fact at all that in a powderpreparation for intratracheobronchial administration, there may occursignificant adhesion and/or adsorption of fine particles comprising amain medicament. It will be understood that to the present inventor'sknowledge, the fact that the above adhesion adsorption phenomenon can beavoided by use of receptacles composed of hydroxypropyl methyl celluloseor the like, is novel and cannot be anticipated at all from the hithertoknown literature or the like.

DISCLOSURE OF INVENTION

The purpose of the present invention is to provide a preparation forintratracheobronchial administration, which prevents the fine particlescontaining medicament from being adhered or adsorbed to the innersurfaces of the receptacles, so that the amount of the medicamentdelivered into the airway is improved.

More specifically, the purpose of the present invention is to provide apreparation for intratracheobronchial administration, which does notreduce the amount of the preparation delivered from receptacles to theairway, even if the preparation is stored under dry conditions.

In accordance with the present invention, there is provided apreparation for intratracheobronchial administration, which is containedin receptacles composed of at least one component selected from thegroup consisting of hydroxypropyl methyl cellulose, methyl cellulose,hydroxypropyl cellulose, starches, hydroxypropyl starches, and sodiumalginate.

The present inventors have repeated their studies for settling theaforesaid problem, and found the astonishing fact that when a powderpreparation for intratracheobronchial administration is contained inreceptacles composed essentially of a cellulose derivative or analogue,i.e. a receptacle composed of at least one component selected from thegroup consisting of hydroxypropyl methyl cellulose, methyl cellulose,hydroxypropyl cellulose, starches, hydroxypropyl starches, and sodiumalginate, the above-mentioned problem can be settled, and finallyreached the present invention.

The adhesion/adsorption to the inner surface of receptacles of themedicament particles, or the particles comprising medicaments, containedin a receptacle is related to various factors including, for example,(1) the physical properties of the receptacle, (2) the physicalproperties of the medicament, (3) the physical properties of theparticles of the additives copresent with the medicament particles andthe particles comprising the medicament and (4) the environmentalfactors such as humidity is complicated.

It is clearly found as a result of our study heretofore that, when themedicament particles or particles comprising medicaments only are finelydivided to a particle size necessary for the preparation forintratracheobronchial administration, i.e., about 500 μm or lessirrespective of the presence of conventional additives, it isunavoidable irrespective of the physical properties and kinds of themedicament that the particles are adhered and adsorbed to conventionalreceptacles such as gelatin capsules, aluminum disks, polyethylenereceptacles, but are not adhered and adsorbed to the receptaclesaccording to the present invention. It is not clear why, to receptaclesmainly composed of cellulose derivatives and analogues such ashydroxypropyl methyl cellulose, methyl cellulose, hydroxypropylcellulose, starch, hydroxypropyl starch, sodium alginate, theabove-mentioned particles are not adhered and adsorbed, due to the factsthat the factors are complicated as mentioned above and the analysisthereof is difficult. However, these cellulose derivatives and analoguesare not statically charged when contacted with the medicament particlesor additive particles, but it is confirmed by our experiments that thestatical charge occurs in the case of gelatin, polyethyleneconventionally used as the receptacles.

BEST MODE FOR CARRYING OUT THE INVENTION

With respect to the shape of the receptacles used in the presentinvention, composed of hydroxypropyl methyl cellulose or the like, theremay be adopted either a type, in which the preparation is preliminarilydivided into each dose to be delivered into the airway for one time andeach dose of the preparation is contained in each receptacle (unit dosetype), or a type, in which the powder preparations for a plurality ofdoses are contained in a lump in a receptacle, such that a dose ofpowder preparation is divided from the receptacle and delivered into theairway by some means, every time the powder preparation is to be used(multidose type). In the case of a unit dose type, the receptacles mayassume the shape of medical hard capsules, or the shape such that a unitdose is divided into some pieces and these pieces are contained in areceptacle on some places of the disk surface of the receptacle moldedinto a disk-shaped product. In addition, the receptacle may be moldedinto a proper shape in conformity with the shape of an administeringutensil, and also may be a disposable receptacle integrated with anadministering utensil. As a multidose type receptacle, any suffices ifit is adequately molded in conformity with a multidose typeadministering utensil and has such a shape as has a function necessaryto be charged in the multidose type administering utensil, when used,and put to practical use.

Although the proportion of hydroxypropyl methyl cellulose or the likebased on the weight of a receptacle composed of the hydroxypropyl methylcellulose or the like is limited by the hereafter-mentioned productionprocess for the receptacle, it is preferably 70% by weight or more, andmore preferably 80% by weight or more when a receptacle is composed oftwo or more kinds of components, the total weight of these components isdesirably within the above range.

As the compounds to be compounded in a receptacle used in the presentinvention, composed of hydroxypropyl methyl cellulose or the like, thereare mentioned plasticizers, thickening agents, auxiliary agents thereof,coloring matters, and the like. Specifical examples of these compoundsare e.g. polyvinyl alcohol, polyethylene glycol, sorbitol, mannitol,sucrose, carrageenan, sodium chloride, potassium chloride, titaniumoxide, lake coloring matter, and the like.

The receptacle is produced by use of at least one compound selected fromthe group consisting of hydroxypropyl methyl cellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, andsodium alginate. Of these compounds, hydroxypropyl methyl cellulose isfavorable. As hydroxypropyl methyl cellulose to be used, with respect tothe substitution ratio of the cellulose ether thereof, there ispreferred one having a methoxyl group weight ratio ranging from 15 to30% and a hydroxypropoxyl group weight ratio ranging from 3 to 15%, andwith respect to the viscosity of the cellulose ether thereof, there isfurthermore desired one having a viscosity of a 2% aqueous solution at20° C., ranging from 2 to 20 cps. In addition, of usable hydroxypropylmethyl celluloses, with respect to the substitution ratio of thecellulose ether thereof, there are furthermore preferred hydroxypropylmethyl celluloses having a methoxyl group weight ratio ranging from 19to 30% and a hydroxypropoxyl group weight ratio ranging from 4 to 12%.Further, as the hydroxypropyl methyl cellulose to be used, with respectto its viscosity, more desirable ones are hydroxymethyl celluloseshaving a viscosity of a 2% aqueous solution at 20° C., ranging from 3 to15 cps.

The receptacle used in the present invention, composed essentially ofhydroxypropyl cellulose, can be prepared in the same manner as a methodfor the preparation of hard gelatin capsules which have often been usedas medical capsules. With respect to the details of the productionprocesses of the capsules, there are disclosed in, e.g. JapaneseUnexamined Patent Publication No. 61-100519, Japanese Unexamined PatentPublication No. 62-266060, Japanese Unexamined Patent Publication No.63-127757, and Japanese Unexamined Patent Publication No. 3-9755. Itwill be easily understood that by these processes, there can be moldedall the kinds of unit dose-type and multidose-type receptacles usablefor powder preparations for intratracheobronchial administration,including medical capsules.

The powder preparation for intratracheobronchial administration, used inthe present invention, comprises a medicament alone, revealing apharmacological effect, or the medicament revealing the pharmacologicaleffect and additives.

Of the medicaments revealing pharmacological effects, as a medicamentrevealing a pharmacological effect at an affected part in the airway,there are mentioned e.g. steroidal antiinflammatory drugs such ashydrocortisone, prednisone, prednisolone, triamcinolone, triamcinoloneacetonide, dexametlon, betamethasone, beclometasone, and beclometasonedipropionate; non-steroidal antiinflammatory drugs such asacetoaminophenone, phenacetin, aspirin, aminopyrin, sulpyrine,phenylbutazone, mefenamic acid, ibufenac, ibuprofen, alclofenac,dichlofenac sodium, indomethacin, colchicine, and probenecid; enzymaticantiinflammatory drugs such as chymotrypsin, promelaincerapetase;antihistamines such as diphenhydramine hydrochloride, chloropheniraminemaleate, and clemastine; antiallergic agents (antitussive, expectorantand antastimatic drugs) such as disodium cromoglycate, codeinephosphate, and isoproterenol hydrochloride; antibiotics such astetracycline hydrochloride, leucomycin, fradiomycin, penicillin, and thederivatives thereof, and erythromycin; chemotherapeutants such assulfathiazole, and nitrofurazone; local anesthetics such as benzocaine;vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozolinehydrochloride, naphazoline nitrate, oxymethazoline hydrochloride, andtramazoline hydrochloride; cardiac stimulants such as digitalis, anddigoxin; vasolators such as nitroglycerine and papaverine hydrochloride;antimicrobial agents such as chlorophexidine hydrochloride, hexylresorcin, decalinium hydrochloride, and ethacrydine; enzymes such aslysothium chloride, and dextranase; anticancer drugs such asfurfonracil; erasrase inhibitors; sympathomimetic drugs such assalbutamol sulfate, procaterol hydrochloride, and orciprenaline, andphenoterol hydrobromide; parasympatholytic drugs (cholinergic blockingagents) such as ipratropium, and furtropium oxalate; sputum-solubilizingdrugs such as acetyl cysteine sodium, and bromhexine; mucous-lubricatingagents such as ambroxol; and the like.

In addition, of the medicaments revealing pharmacological effects, asthe medicaments which are absorbed in the body fluid such as blood fromthe airway and reveal pharmacological effects to the whole body, thereare mentioned peptides, proteins, i.e. polypeptides, having variousphysiological activities. Of the polypeptides, those having a molecularweight ranging from 300 to 300,000 are preferable, because thesepolypeptides are easily absorbed through the tracheobroncheal mucosa.The molecular weight of the polypeptides is especially preferably withinthe range between 1,000 and 150,000. As specifical examples ofpolypeptides having physiological activities, there are mentioned thefollowing: e.g. peptide hormones such as insulin, angiotensin,vasopressin, desmopressin, felypressin, protylylene, luteinizinghormone, corticotropin, prolactin, somatropin, thyrotropin, luteinizinghormone, calcitonin, kallikrein, parathylin, glucagon, oxitocin,gastrin, secretin, serum gonadotropin, growth hormone, erythropoietin,angiotensin, urogastrone, renin, lypomodulin, calmodulin, and hANP(human Atrial Naturetic Polypeptide), the chemically modified compoundsthereof or components thereof; biologically active proteins such asinterferon, interleukin, transferrin, histaglobulin, macrocortin, andserum coagulator VIII; enzyme proteins such as lysozyme, and urokinase.

In addition, of the medicaments revealing pharmacological effects, asvaccines utilizing the antigen recognition function of the lymphorganization in the airway, there may be mentioned pertussis vaccine,diphtheric vaccine, tetanus vaccine, influenza vaccine or lymphocyteincreasing factor, fibrous leukocyte agglutinizing elements, and thelike.

Among the medicaments used in the present invention, revealing theabove-mentioned pharmacological effects, it is preferable to use themedicaments such that the physical loss due to the adhesion andadsorption thereof to the inner surface of the receptacles is thesubstantial loss of the administration amount, namely a smalladministration amount of a highly active medicament. The amount of theadhesion and adsorption to the inner surface of the receptacle largelydepends upon 10 the contact area between the preparation and the innersurface of the receptacle. For example, when beclometasone dipropionatepowder having a particle size of 5-10 μm is contained in a #2 gelatincapsule, the amount of adhesion and adsorption is about 10 μg. It shouldbe, however, noted that the loss of the medicament due to the adhesionand adsorption is varied depending upon the shapes of the receptaclesand the size of the receptacles based upon a unit dose or a multidose.Nevertheless, based upon the above-mentioned example of thebeclometasone dipropionate, if it is assumed that the maximum amount ofabout 100 μg is lost for each dose, the administration amount, in whichthe above-mentioned amount of loss is substantial loss in theadministration amount, is about 2 mg per one dose at maximum.Accordingly, it is not limited, but the use of the medicaments having aunit dose in one administration of about 2 mg or less is preferable.More specifically, the favorable ones are steroidal antiinflammatorydrugs, sympathomimetic drugs, parasympatholytic drugs, peptides,proteins and vaccines.

Furthermore, the adhesion and adsorption to the receptacle areespecially remarkable in the dried state, and therefore, the presentinvention is especially preferable in the case of medicaments which aredried for the stabilization. Examples of such medicaments are peptides,proteins, vaccines.

As the additives used together with the medicaments revealingpharmacological effects in the powder preparation forintratracheobronchial administration, used in the present invention,there may be used the additives which have hitherto been used in powderpreparations for intratracheobronchial administration, or any additivemay be used, as long as it is usable. As such additives, pharmaceuticalvehicles are used, and as concrete examples thereof, there may bementioned one or a plurality of members selected from cellulose ethers,water absorbent and slightly water soluble base materials, sugars, aminoacids and the like.

Cellulose ethers are cellulose derivatives in which a plurality ofhydroxyl groups of cellulose are at least partially etherified, andexamples thereof include e.g. lower alkyl ethers of celluloses, lowerhydroxyalkyl ethers, lower carboxyalkyl ethers, and the like. The ethergroups are not necessarily limited to same kinds, and e.g. celluloseethers having 2 or more kinds of ether groups, e.g. a lower alkyl groupand a lower hydroxyl alkyl group in a molecule are included in thecellulose ethers of the above category. Of these cellulose ethers, loweralkyl ethers of celluloses or lower hydroxyalkyl ethers are favorablyused. The term, "lower alkyl" herein referred to means an alkyl groupwith 5 or less carbon atoms, preferably 3 or less carbon atoms.

As the above-mentioned cellulose ethers, there may be mentioned methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, carboxyethyl cellulose,carboxymethylhydroxy cellulose, hydroxypropyl methyl cellulose, and thelike. Among them, there is preferably used especially methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose.

As the cellulose ethers, e.g. those having a viscosity of the 2% byweight aqueous solution thereof at 20° C., ranging from 3 to 100,000centipoises, more preferably from 3 to 10,000 centipoises, especiallypreferably from 6 to 6,000 centipoises are preferably used.

As the cellulose ethers, e.g. those having an ether substitution degreeranging from 0.1 to 6.0, especially from 0.4 to 4.6 are preferably used.The term, "ether substitution degree", herein referred to means theaverage number of ether groups per glucose unit composing the cellulose,with regard to three hydroxyl groups of said one unit.

As the water absorbable and slightly water soluble bases, there may bementioned e.g. water absorbable and slightly water soluble cellulosessuch as crystalline cellulose, α-cellulose, and cross-linkedcarboxymethyl cellulose sodium; water absorbable and slightly watersoluble starches such as hydroxypropyl starch, carboxymethyl starch,cross-linked starch, amylose, amylopectin, and pectin; water absorbableand slightly water soluble proteins such as gelatin, casein, and caseinsodium; water absorbable and slightly water soluble gums such as gumArabic, gum tragacanth, and glucomannan; cross-linked vinyl polymerssuch as polyvinyl polypyrrolidone, cross-linked polyacrylic acid and thesalts thereof, cross-linked polyvinyl alcohol, and polyhydroxymethylmethacrylate. Of these bases, water absorbable and slightly watersoluble celluloses are preferable, and especially crystalline celluloseis favorable.

As the sugars, there may be mentioned glucose, annitol, lactose,fructose, dextran, and the like.

As the amino acids, there may be mentioned glycine, alanine and thelike. In addition, besides these pharmaceutical vehicles, there areadded, if necessary, a dispersion auxiliary agent, lubricant,stabilizer, and the like.

Now, the above-mentioned additives and the medicaments exhibiting thepharmacological effects may be present in the separate particles in thepreparations or may form the same particles together. In the formercase, the additives and the medicaments can be mixed, for example,mechanically. In the latter case, the additives and the medicament maybe dispersed or dissolved in a solvent or solvents, followed by, forexample, spray drying to form the preparation.

Now, the preparation for intratracheobronchial administration from theabove-mentioned receptacle and powder preparation (comprising amedicament alone or the medicament and additives) is described. Theproduction process thereof varies according to the aimed region in theairway, to which the medicament is to be delivered. That is, asdescribed above, it is said that the region in the airway, to which amedicament can be delivered, is determined in accordance with theparticle diameter of a preparation; e.g. particles with a particlediameter of more than about 10 μm, but not more than about 500 μm aredeposited mainly in the oral cavity and nasal cavity, those having aparticle diameter more than 2 μm but not more than 10 μm are depositedmainly in the trachea, bronchi, and bronchiole, and those having aparticle diameter ranging from 0.5 to 2 μm are deposited mainly in thealveoli. Therefore, by adjusting the particle diameter of the powderpreparation, it is possible to efficiently deliver the medicament to thetargeted region. Perferably, at least 80 percent by weight of theparticles in the powder preparation will have a diameter ranging fromabout 0.5 to 149 μm.

First, in order to deliver the medicament in the oral cavity and nasalcavity, it suffices, if the particle diameter of the powder preparationto be contained in the receptacles of the present invention is adjustedto a value greater than 10 μm, but not more than 500 μm. Among suchpowder preparations, as an example of preparation for topicalapplication, there may be mentioned e.g. a curative medicine for nasalallergy, which is obtained by mixing e.g. beclometasone dipropionate, asteroidal antiinflammatory drug, having a particle diameter of more than10 μm, but not more than 500 μm and hydroxypropyl cellulose, an additivehaving a particle diameter of more than 10 μm, but not more than 500 μmby a mixer. In the above case, in order to maintain the effect of themedicament for a long time, as the additives to be compounded into thepreparation together with the main ingredient of the preparation,cellulose esters such as the exemplified hydroxypropyl cellulose arepreferable. As other drugs for local application, there may be mentionedthe other steroidal antiinflammatory drugs, non-steroidalantiinflammatory drugs, enzymatic antiphlogistics, antihistamic agents,antiallergic agents, vasoconstrictors, and the like. In addition, amongthe same kinds of powder preparations as above, as medicines for wholebody, there are mentioned, e.g. transnasal preparations, the mainmedicament of which is proceeded to the vascular flow through the nasalmucosa and exhibits systemic action, and these transnasal preparationsare prepared by mixing e.g. calcitonin with a particle size larger than10 μm, but not more than 500 μm, e.g. salmon calcitonin withmicrocrystalline cellulose with a particle size larger than 10 μm, butnot more than 500 μm by a mixer. In the above case, in order to obtainrapid onset of medical effect and good absorption, as the additives tobe compounded into the preparation together with the main medicament,there are preferred the water absorbent and slightly water soluble basesas exemplified above. As the other medicaments for whole body, there maybe mentioned peptides other than calcitonin, polypeptides such asproteins, vaccines, and the like.

Next, in order to deliver the medicament into the trachea, bronchi,bronchioles, and alveoli, it suffices, if the particle diameter of thepowder preparation to be contained in the receptacles of the presentinvention is adjusted within the range between 10 μm and 0.5 μm. In theabove case, all the particles do not necessarily need to have a particlediameter within the above range, but the more of whole amount of theparticles having a particle diameter within the above range, the morethe amount of the particles delivered into the trachea, bronchi,bronchioles, and alveoli.

Of these powder preparations, as medicament for local effect, there maybe mentioned e.g. an antiasthmatic agent, which is prepared by makinge.g. beclometasone dipropionate, a steroidal antiinflammatory drugs, andhydroxypropyl cellulose, an additive, and spray drying the mixture asfine particles having a particle diameter ranging from 10 to 0.5 μm. Asother medicaments for local action, there may be mentioned the othersteroidal antiinflammatory drugs, non-steroidal antiinflammatory drugs,enzymatic antiinflammatory drugs, antiallergic agents, antihistamicagents, elastase inhibitors, sympathomimetic drugs, parasympatholyticdrugs, keratolytic drugs, mucosa swelling agents, and the like.

In addition, of the same kinds of preparations as above, as medicamentfor systemic effect, there may be mentioned a transpulmonarypreparation, the main medicament of which proceeds into the vascularflow through the alveolo mucosas and exhibits systemic effect, which isobtained by making e.g. insulin and dextrose into fine particles havinga particle diameter ranging from 10 to 0.5 μm. As other medicaments forwhole body effect, there may be mentioned other peptides, polypeptidessuch as proteins, and the like. As the additives used in these powderpreparations to be delivered into the trachea, bronchi, bronchioles, andalveoli, slightly stimulative and water soluble ones are desirable, ande.g. sugars, amino acids, and water soluble cellulose ethers arepreferable.

The preparation of the present invention is administered into therespiratory tract through the nasal cavity or oral cavity, and the powersource necessary for the preparation of the present invention, containedin the receptacles, to be introduced into the airway through the nasaland oral cavities, may be either the breathed air (inhalation) of apatient himself or a power source other than the breathed air of thepatient, e.g. a balloon method or the like.

The powder preparation for intratracheobronchial administration, used inthe present invention, is contained in the aforesaid receptacles used inthe present invention, composed of the components such as hydroxypropylmethyl cellulose or the like, and thereby obtained in the form of apreparation. The shape of the receptacles is selected in conformity withthe structure of the administering utensil, and therefore, the structureof the administering utensil is significant.

The structure of the administering utensil used when administering thepowder preparation of the present invention is subjected to norestriction, as a general rule, and any administering utensil may beused, as long as it is the administering utensil (administering device)which has hitherto been used or proposed. As a unit dose typeadministering utensil, there may be mentioned e.g. the powderpreparation-administering device (Japanese Examined Patent PublicationNo. 63-6024) corresponding to the medical hard capsule, "Spinhaler"(Registered Trade Mark), "Rotahaler" (Registered Trade Mark),"Diskhaler" (Registered Trade Mark) and the like.

In addition, as administering utensil corresponding to the multidosetype receptacles, there may be mentioned e.g. "Turbohaler" (RegisteredTrade Mark), and the like.

Industrial Applicability

As explained above, according to the present invention, when apreparation for intratracheobronchial administration comprising a powderpreparation for intratracheobronchial administration contained inreceptacles composed of hydroxypropyl methyl cellulose or the like isadministered into the airway by such an administering utensil asdescribed above, the powder preparation is adhered or adsorbed to thereceptacle inner surfaces in a less amount than the case where a powderpreparation contained in conventional receptacles is administered intothe airway by such an administering utensil as above, so that the amountof the present powder preparation actually delivered into the airway islarger, which fact is very meaningful in view of the curative effect.

EXAMPLES

The present invention will now be further explained in detail withreference to the Examples, but it is to be noted that the presentinvention is not limited thereto.

Examples 1 to 16, Control Examples 1 to 64

The following experiments were performed for the purpose of clarifyingthat a powder preparation for intratracheobronchial administrationexhibits only slight adhesiveness/adsorptiveness to receptacles composedessentially of hydroxypropyl methyl cellulose.

(1) Production of a measuring box for the amount of the powderpreparation adhered/adsorbed to various receptacle materials:

A box having one square base with a side length of 2 cm and a height of1 cm, the other base being opened, was made of a cardboard, and a thinfilmy material described in the following item (2) was stuck to the 5faces confronting the inside of the box (4 lateral faces and one base)with "Alon alpha" (produced by Toa Gosei Kagaku).

(2) Preparation of the thin filmy material to be stuck to the innerfaces of the measuring box for adhered/adsorbed amount:

As described in the following, there were prepared five kinds ofmaterials including the material composed essentially of hydroxypropylmethyl cellulose.

Material A: A thin film with a thickness of 0.1 mm, consisting of 93parts by weight of hydroxypropyl methyl cellulose (produced by ShinetsuKagaku, trade name: "TC-5R": methoxyl group: 28 to 30% by weight,hydroxypropoxyl group: 7 to 12% by weight, viscosity of a 2% aqueoussolution at 20° C.: 6 cps), 1 part by weight of carrageenan (produced byWako Junyaku), 1 part by weight of potassium chloride (produced by WakoJunyaku), and 5 parts by weight of water. (A solution obtained bydissolving above substances in an excessive amount of water was spreadon a flat plate, and dried so as to be formed into a uniform filmyproduct.)

Material B: A thin film with a thickness of 0.1 mm, consisting of 95parts by weight of gelatin (produced by Wako Junyaku) and 5 parts byweight of water. (A solution obtained by dissolving the gelatin in anexcessive amount of water was spread on a flat plate, and dried so as tobe formed into a uniform filmy product.)

Material C: Polypropylene sheet (A sheet produced by Nikko was used assuch.)

Material D: Aluminium foil (A Nippaku foil was used as such.)

Material E: Ordinary thin sheet glass.

(3) Preparation of a powder preparation for intratracheobronchialadministration, comprising a medicament:

The medicaments, bases, and lubricants described in Table 1 weremix-prepared by the methods described in Table 1, respectively, so thatpowder preparations for intratracheobronchial administration wereprepared. The particle size distributions of the prepared powderpreparations are also set forth in Table 1.

(4) Method of determining the amount of the adhered and adsorbedmedicament:

Each 100 mg of the powder preparations for intratracheobronchialadministration, prepared in the above (3) were introduced into themeasuring boxes described in (1), which had been lined, respectively,with the materials described in (2), and each of the boxes was shakedright and left by a shaker, so that each powder preparation was broughtinto contact with each material. During the shaking operation, the topopen face was covered in order to prevent the content of the box frombeing scattered. (These experiments were performed under the conditionsof 25° C./40% RH.) After the shaking operation had been completed, thelid was removed and the contents were taken out. The powder preparationswere, respectively, discharged by tapping the box with a spatula, or byother means, until the powder preparation could not be recognized withnaked eyes on the base and lateral faces of the box. The dischargedpowder preparations were collected and the medicament contained thereinwas measured by high speed liquid chromatography, whereupon the amountof powder preparation adhered or adsorbed in the inner faces of the boxwas calculated on the basis of the amount of the powder preparationinitially introduced in the box. The results of Examples 1 to 16, withvariation of the combinations of the receptacle materials and powderpreparations, are set forth in Table 2, and the results of ContrastExamples 1 to 64, with variation of the combinations of the conventionalreceptacle materials and powder preparations are set forth in Table 3.

                                      TABLE 1                                     __________________________________________________________________________    Powder                       Prepa-                                           Prep.                        ration                                           No.   Medicament                                                                            Base     Lubricant                                                                           method                                                                            Remarks                                      __________________________________________________________________________    1     Salmon  Microcrystalline                                                                       Magnesium                                                                           a   Preparation                                        calcitonin.sup.1)                                                                     cellulose.sup.10)                                                                      stearate.sup.15)                                                                        for nasal                                          (100 I.U.)                 cavity                                       2     Salmon  Cross-linked                                                                           Magnesium                                                                           a   Preparation                                        calcitonin.sup.1)                                                                     starch.sup.11)                                                                         stearate.sup.15)                                                                        for nasal                                          (100 I.U.)                 cavity                                       3     Insulin.sup.2)                                                                        Microcrystalline                                                                       Magnesium                                                                           a   Preparation                                        (5 I.U.)                                                                              cellulose                                                                              stearate.sup.15)                                                                        for nasal                                                                     cavity                                       4     Insulin.sup.2)                                                                        Hydroxypropyl                                                                          Magnesium                                                                           b   Inhalant                                           (5 I.U.)                                                                              cellulose.sup.12)                                                                      stearate.sup.15)                                       5     Insulin.sup.2)                                                                        Hydroxypropyl                                                                          Magnesium                                                                           c   Inhalant                                           (5 I.U.)                                                                              cellulose.sup.12)                                                                      stearate.sup.15)                                       6     LHRH.sup.3)                                                                           Microcrystalline                                                                       Magnesium                                                                           a   Preparation                                        (400 μg)                                                                           cellulose                                                                              stearate.sup.15)                                                                        for nasal                                                                     cavity                                       7     LHRH.sup.3)                                                                           Lactose.sup.13)                                                                        Magnesium                                                                           b   Inhalant                                           (400 μg)      stearate.sup.15)                                       8     LHRH.sup.3)                                                                           Hydroxypropyl                                                                          Magnesium                                                                           c   Inhalant                                           (400 μg)                                                                           cellulose                                                                              stearate.sup.15)                                       9     Beclometasone                                                                         Hydroxypropyl                                                                          Magnesium                                                                           a   Preparation                                        dipropionate.sup.4)                                                                   cellulose                                                                              stearate.sup.15)                                                                        for nasal                                          (400 μg)                cavity                                       10    Beclometasone                                                                         Lactose  Magnesium                                                                           b   Inhalant                                           dipropionate.sup.4)                                                                            stearate.sup.15)                                             (400 μg)                                                             11    Beclometasone                                                                         Hydroxypropyl                                                                          Magnesium                                                                           c   Inhalant                                           dipropionate.sup.4)                                                                   cellulose                                                                              stearate.sup.15)                                             (400 μg)                                                             12    Salbutamol                                                                            Hydroxypropyl                                                                          Magnesium                                                                           b   Inhalant                                           sulfate.sup.5)                                                                        cellulose                                                                              stearate.sup.15)                                             (100 μg)                                                             13    Ipratropium                                                                           Hydroxypropyl                                                                          Magnesium                                                                           c   Inhalant                                           bromide.sup.6)                                                                        cellulose                                                                              stearate.sup.15)                                             (40 μg)                                                              14    Triamcinolone                                                                         Hydroxypropyl                                                                          Magnesium                                                                           a   Preparation                                        acetonide.sup.7)                                                                      methyl   stearate.sup.15)                                                                        for nasal                                          (400 μg)                                                                           cellulose.sup.l4)  cavity                                       15    Procaterol                                                                            Hydroxypropyl                                                                          Magnesium                                                                           b   Inhalant                                           hydrochloride.sup.8)                                                                  methyl   stearate.sup.15)                                             (50 μg)                                                                            cellulose.sup.l4)                                               16    Fenoterol                                                                             Hydroxypropyl                                                                          Magnesium                                                                           c   Inhalant                                           hydrobromide.sup.9)                                                                   cellulose                                                                              stearate.sup.15)                                             (200 μg)                                                             __________________________________________________________________________     .sup.1) produced by Sigma Inc.                                                .sup.2) produced by Sigma Inc.                                                .sup.3) produced by Peptide Research Institute                                .sup.4) produced by Sigma Inc.                                                .sup.5) produced by Sigma Inc.                                                .sup.6) produced by Sigma Inc.                                                .sup.7) produced by Sigma Inc.                                                .sup.8) produced by Sigma Inc.                                                .sup.9) produced by Sigma Inc.                                                .sup.10) "Apicel PH101" produced by Asahi Kasei                               .sup.11) produced by Nichiden Kagaku                                          .sup.12) "HPCH" produced by Nippon Soda Inc.                                  .sup.13) produced by Megle                                                    .sup.14) "TC5R" produced by Shinetsu Kagaku                              

In Table 1, the content in 30 mg of each powder preparation was shown ineach pair of parentheses. In addition, the content of magnesium stearatewas 0.5% by weight of each powder preparation. Mix-preparation waseffected in the following manner.

a) To a predetermined amount of the medicament having a particlediameter of 46-149 μm, there was added a base having 90% by weight ormore of particles with a particle diameter ranging from 46-149 μm,followed by mixing in a small-sized V-type mixer until the mixturebecomes uniform and finally 0.5% of magnesium stearate was mixed to theobtained mixture, whereby a homogeneous powder preparation forintranasal administration was obtained.

b) To a predetermined amount of the medicament having a particlediameter of 0.5-10 μm, there was added a base having 90% or more ofparticles with a particle diameter of 46-149 μm, followed by mixing in asmall-sized v-type mixer until the mixture becomes uniform, and finally0.5% of magnesium stearate was mixed to the obtained mixture, whereby ahomogeneous powder preparation for internasal administration wasobtained.

c) A predetermined amount of a medicament and base were dissolved into asolvent composed essentially of water (ethanol was added, if necessary),and the obtained solution was spray dried to prepare a powder of minuteparticles, whereafter 0.5% of magnesium stearate was added to theobtained powder, so that a powder preparation (inhalant) forintratracheobronchial administration was obtained.

The particle size distribution of the powder preparations obtained bythe above-mentioned preparing method c) was 0.5 to 10 μm for 80% or morethereof. The results obtained by use of a laser type particle sizemeasuring machine (JEOL/SYMPATEC; HEROS & ROODS).

                  TABLE 2                                                         ______________________________________                                                Receptacle Powder     Adhering/Adsorbing                              Example Material   Preparation                                                                              Rate (%)                                        ______________________________________                                        1       A          1          2                                               2       A          2          3                                               3       A          3          3                                               4       A          4          7                                               5       A          5          8                                               6       A          6          4                                               7       A          7          6                                               8       A          8          7                                               9       A          9          2                                               10      A          10         4                                               11      A          11         7                                               12      A          12         2                                               13      A          13         3                                               14      A          14         3                                               15      A          15         4                                               16      A          16         5                                               ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                                Receptacle Powder     Adhering/Adsorbing                              Example Material   Preparation                                                                              Rate (%)                                        ______________________________________                                        1       B          1          15                                              2       "          2          18                                              3       "          3          20                                              4       "          4          23                                              5       "          5          26                                              6       "          6          17                                              7       "          7          19                                              8       "          8          25                                              9       "          9          19                                              10      "          10         18                                              11      "          11         27                                              12      "          12         20                                              13      "          13         16                                              14      "          14         19                                              15      "          15         20                                              16      "          16         24                                              17      C          1          31                                              18      "          2          28                                              19      "          3          34                                              20      "          4          45                                              21      "          5          49                                              22      "          6          30                                              23      "          7          35                                              24      "          8          37                                              25      "          9          29                                              26      "          10         26                                              27      "          11         46                                              28      "          12         36                                              29      "          13         33                                              30      "          14         29                                              31      "          15         32                                              32      "          16         43                                              33      D          1          18                                              34      "          2          19                                              35      "          3          21                                              36      "          4          23                                              37      "          5          30                                              38      "          6          20                                              39      "          7          20                                              40      "          8          28                                              41      "          9          16                                              42      "          10         18                                              43      "          11         21                                              44      "          12         15                                              45      "          13         17                                              46      "          14         19                                              47      "          15         20                                              48      "          16         22                                              49      E          1          19                                              50      "          2          18                                              51      "          3          18                                              52      "          4          25                                              53      "          5          27                                              54      "          6          16                                              55      "          7          17                                              56      "          8          21                                              57      "          9          15                                              58      "          10         14                                              59      "          11         28                                              60      "          12         13                                              61      "          13         14                                              62      "          14         15                                              63      "          15         16                                              64      "          16         23                                              ______________________________________                                    

From Table 2 and Table 3, it can be seen that theadhesiveness/adsorptiveness of the powder preparation forintratracheobronchial administration to receptacles composed essentiallyof hydroxypropyl methyl cellulose is less than that to receptacles madeof gelatin, polypropylene, aluminium foil or glass.

Examples 17-21, Control Examples 65-69

The powder preparations 1, 3, 6, 9 and 14 described in the above Table 1were filled up into medical hard capsules composed essentially ofhydroxypropyl methyl cellulose (composition: 93 parts by weight ofhydroxypropyl methyl cellulose, "TC-5R" produced by Shinetsu Kagaku; 1part by weight of carrageenan; 1 part by weight of potassium chloride; 5parts by weight of water), in an amount of 30 mg, respectively, and,after storing at 25° C. and 55% RH for 2 weeks, the powder preparationswere sprayed by a powder preparation-administering device (JapaneseExamined Patent Publication No. 63-6024) until the powder preparationcould not be recognized with naked eyes, following which theabove-mentioned capsules were taken out and the medicament remained inthe capsule inner faces was subjected to measurement by HPLC, wherebythe adhesion-adsorption ratio of the powder preparation to the capsuleinner faces was calculated. (Examples 17-21).

In addition, the powder preparations 1, 3, 6, 9, and 14 also describedin the above Table 1 were, respectively, filled up into each of medicalcapsules composed essentially of gelatin (composition: 95 parts ofgelatin and 5 parts by weight of water) in an amount of 30 mg, whereuponthe same experiments as described in Examples 17 to 21 were conducted.(Control Examples 65-69).

The results are set forth in Table 4.

                  TABLE 4                                                         ______________________________________                                                   Rate of Adhesion/Adsorption (%)                                               25° C./55% RH                                                                      Drying Conditions                                      ______________________________________                                        Example                                                                       17           2             4                                                  18           4             5                                                  19           3             5                                                  20           5             7                                                  21           5             7                                                  Control Example                                                               65           9             25                                                 66           13            43                                                 67           10            39                                                 68           19            47                                                 69           25            46                                                 ______________________________________                                    

It may be seen from Table 4 that the proportion of the powderpreparation for intratracheobronchial administration remained in theinsides of capsules, when the powder preparation filled in the capsulescomposed essentially of hydroxypropyl methyl cellulose is sprayed from apowder preparation-administering device, is less than the proportion ofthe preparation remained when the preparation is filled in gelatincapsules and simultaneously sprayed, and also that the amounts of theadhesion/adsorption are not affected by the drying. Note that there aresome gelatin capsules causing cracks during drying.

Examples 22, 23, and Contrast Examples 70 and 71

The powder preparations 4 and 11 described in the above Table 1 werefilled up in medical hard capsules composed essentially of hydroxypropylmethyl cellulose in an amount of 5 mg, respectively, like Examples 17 to21, and holes were made in the capsules by use of a powderpreparation-administering device in the same way as described in theabove Examples 17 to 21, following which a suction pump was connected tothe device and the contents of the capsules were sucked at a rate of 60liter/min by this suction pump, whereafter the amount of main medicamentremained on the capsule inner faces was determined by the similar way,so that the rate of the medicament adhered to the capsule inner faceswas calculated (Examples 22 and 23).

The same experiments were performed also with respect to the same powderpreparations 4 and 11 filled up in gelatin capsules, whereby the ratesof the powder preparations adhered to the capsule inner faces werecalculated, respectively. (Contrast Examples 70 and 71).

The results are set forth in Table 5.

                  TABLE 5                                                         ______________________________________                                                     Rate of Adhesion/Adsorption                                      ______________________________________                                        Example 22     5                                                              Example 23     4                                                              Contrast Example 70                                                                          18                                                             Contrast Example 71                                                                          23                                                             ______________________________________                                    

It can be seen from Table 5 that the proportion of the contents of apowder preparation for intratracheobronchial administration, remained inthe insides of capsules, when the contents of the preparation filled upin capsules composed essentially of hydroxypropyl methyl cellulose aresucked in the same manner as human inhalation is less than theproportion of the preparation remained in gelatin capsules when thecontents of the preparation filled up in the gelatin capsules are suckedin the same way as above.

Examples 24 to 28

Thin film-like materials, each composed of the following materials F, G,H, I, and J, respectively, were prepared, in the same way as in Examples1 to 16.

Material F: A thin film with a thickness of 0.1 mm consisting of 95parts by weight of methyl cellulose ("Metholose SM 15" produced byShinetsu Kagaku) and 5 parts by weight of water (A solution obtained bydissolving the methyl cellulose with an excessive amount of cooled waterwas spread on a flat plate, whereafter it was dried so as to form auniform thin film.)

Material G: A thin film with a thickness of 0.1 mm, consisting of 95parts by weight of hydroxypropyl cellulose ("Nisso HPC-M") and 5 partsby weight of water (A solution obtained by dissolving the hydroxypropylcellulose with an excessive amount of cooled water was spread on a flatplate, whereafter it was dried so as to be formed into a uniform thinfilm.)

Material H: A thin film with a thickness of 0.1 nun, consisting of 95parts by weight of starch (Indian corn starch produced by NipponShokuhin Kako [Japan Food Processing Industries Co., Ltd.] and 5 partsby weight of water (The starch was solubilized with boiling water,whereafter the solubilized starch was spread on a flat plate, followingwhich it was dried so as to form a uniform thin film.)

Material I: A thin film with a thickness of 0.1 mm, consisting of 95parts by weight of hydroxypropyl starch ("HPS 101 (W)" produced byFreund Industries Inc.) and 5 parts by weight of water (Thehydroxypropyl starch was solubilized with boiling water, whereafter thesolubilized starch was spread on a flat plate, following which it wasdried so as to form a uniform thin film.)

Material J: A thin film with a thickness of 0.1 mm, consisting of 95parts by weight of sodium alginate (produced by Kimitsu Chemical Inc.)and 5 parts by weight of water (A solution obtained by dissolving thesodium alginate in cool water was spread on a flat plate, followingwhich it was dried to form a uniform thin film.)

For these materials F to J, and the powder preparation 1 of Examples 1to 16, the same experiments as in Examples 1 to 16 were performed,whereby the adhesion/adsorption rates of the powder preparation 1 to thematerials F to J were determined, respectively. The results are setforth in Table 6.

                  TABLE 6                                                         ______________________________________                                                Receptacle Powder     Adhesion/Adsorption                             Example Material   Preparation                                                                              Rate (%)                                        ______________________________________                                        24      F          1          4                                               25      G          1          2                                               26      H          1          3                                               27      I          1          3                                               28      J          1          3                                               ______________________________________                                    

It can be seen from Table 6 that the adhesion/adsorption rates of apowder preparation for intratracheobronchial administration, to thereceptacles, composed essentially of methyl cellulose, hydroxypropylcellulose, starch, hydroxypropyl starch, and sodium alginate,respectively, are low in the same degree as the adhesion/adsorptionrates of the same preparation to a receptacle composed essentially ofhydroxypropyl methyl cellulose.

We claim:
 1. A preparation for intratracheobronchial administrationcomprising a powder preparation for intratracheobronchial administrationcontained in a receptacle comprising at least one component selectedfrom the group consisting of hydroxypropyl methyl cellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, andsodium alignate, wherein the amount of said component is at least 80% byweight of said receptacle, and wherein at least 80% by weight of theparticles in said powder preparation, based on the weight of saidpreparation, have a diameter ranging from about 0.5 to 149 μm.
 2. Apreparation for intratracheobronchial administration as claimed in claim1, wherein said component is hydroxypropyl methyl cellulose.
 3. Apreparation for intratracheobronchial administration as claimed in claim1, wherein said receptacle is molded so as to charged as a unit dose ora multidose in an administering utensil for intratracheobronchialadministration of powder.
 4. A preparation for intratracheobronchialadministration as claimed in claim 3, wherein said receptacle is chargedas a unit dose in the administering utensil for intratracheobronchialadministration of powder, which is a medical hard capsule.
 5. Apreparation for intratracheobronchial administration as claimed in claim1, wherein said receptacle is integrated with an administering utensilfor intratracheobronchial administration of said powder, and isdisposable.
 6. A preparation for intratracheobronchial administration asclaimed in any one of claims 1 or 2-5, wherein said powder preparationfor intratracheobronchial administration is a powder preparation whichis inhaled through a nasal cavity and deposited in the nasal cavity. 7.A preparation for intratracheobronchial administration as claimed in anyone of claims 1 or 2-5, wherein said powder preparation forintratracheobronchial administration is a powder preparation which issprayed into a nasal cavity and deposited in the nasal cavity.
 8. Apreparation for intratracheobronchial administration as claimed in anyone of claims 1 or 2-5, wherein said powder preparation forintratracheobronchial administration is a powder preparation which isinhaled through an oral cavity and deposited in the oral cavity,pharynx, larynx, trachea, bronchi, bronchioles, or alveoli.
 9. Apreparation for intratracheobronchial administration as claimed in anyone of claims 1 or 2-5, wherein said powder preparation forintratracheobronchial administration is a powder preparation which issprayed into a oral cavity and deposited in the oral cavity, pharynx,larynx, trachea, bronchi, bronchioles, or alveoli.
 10. A preparation forintratracheobronchial administration as claimed in any one of claims 1or 2-5, wherein said powder preparation for intratracheobronchialadministration is that comprising a medicament selected from the groupconsisting of antiallergic drugs, steroidal antiinflammatory drugs,non-steroidal antiinflammatory drugs, enzymatic antiinflammatory drugs,antihistamines, antibiotics, germicides, chemotherapeutic drugs,elastase inhibitors, local anesthetics, vasoconstrictors, cardiacs,vasodilators, anti-malignant-tumor drugs, sympathomimetic drugs,sympatholytic drugs, parasympatholytic drugs, sputum solubilizers,mucosa lubricants, peptides, proteins, and vaccines.
 11. A preparationfor intratracheobronchial administration as claimed in claim 10, whereinsaid powder preparation for intratracheobronchial administration furthercomprises a pharmaceutical vehicle to be administered simultaneouslywith said medicament, said pharmaceutical vehicle being selected fromthe group consisting of cellulose ethers; water absorbable and slightlywater soluble celluloses, water absorbable and slightly water solubleproteins; water absorbable and slightly water soluble gums; waterabsorbable and slightly water soluble cross-linked vinyl polymers;sugars; and amino acids.
 12. The preparation for intratracheobronchialadministration as claimed in any one of claims 1 or 2-5, wherein saidpowder preparation for intratracheobronchial administration is thatcomprising a medicament selected from the group consisting of steroidalantiinflammatory drugs, sympathomimetic drugs, parasympatholytic drugs,peptides and proteins.
 13. The powder preparation forintratracheobronchial administration as claimed in claim 12, whereinsaid powder preparation for intratracheobronchial administration furthercomprises a pharamaceutical vehicle to be administration simultaneouslywith said medicament, wherein said pharmaceutical vehicle is selectedfrom the group consisting of water absorbable and slightly water solublecelluloses; water absorbable and slightly water soluble starches; waterabsorbable and slightly water soluble proteins; water absorbable andslightly water soluble gums; and water absorbable and slightly watersoluble cross-linked vinyl polymers.